The ability to respond to stress is an important basic adaptive mechanism, and hypothalamic-pituitary-adrenal (HPA)activation is known to be a central feature of this response. Hyperresponsiveness and/or deficits in recovery of HPA activity to basal levels following stress could have adverse behavioral and physiological consequences for the organism and thus impact negatively on health and even survival. We have shown that fetal ethanol exposure (E) results in HPA hyperresponsiveness, manifested as increased HPA activation and/or delayed recovery following stress. The present proposal will extend our study of E effects on the HPA axis. 1) We will further explore possible mechanisms underlying E-induced changes in HPA activity. Our working hypothesis is that HPA hyperresponsiveness in B offspring results from deficits in feedback regulation of HPA activity. We will systematically examine feedback inhibition in fast, intermediate and slow feedback time domains in nonstressed animals. Fast feedback will be further examined in chronically stressed animals, and slow feedback will be further examined by measuring CORT levels needed to normalize HPA activity when the feedback signal is removed (adrenalectomy). In addition, the alternative and not incompatible possibility that the adrenal and/or pituitary is hyperresponsive to secretagogues will be examined. 2) Possible adverse behavioral consequences of HPA hyperresponsiveness will be examined. We will test the hypothesis that HPA hyperresponsiveness may mediate, at least in part, the behavioral hyperresponsiveness of E animals. The role of corticotropin releasing factor (CRF) in mediating behavioral responses in an aversive task, the elevated plus maze, will be investigated by injecting CRF, either centrally or peripherally, and by testing the effects of the specific CRF antagonist, alpha-helical CRF. 3) Possible adverse physiological consequences of HPA hyperresponsiveness will be examined. We will test the hypothesis that HPA hyperresponsiveness may mediate, either in itself, or through an interaction with hypothalamic- pituitary-gonadal hormones, the deficits in immunocompetence observed in E rats. Immune function will be examined following adrenalectomy and/or gonadectomy by measuring lymphocyte proliferation to mitogens and by quantitation of immunoglobulin production. Type II glucocorticoid receptors on splenocytes and thymocytes will also be measured. The proposed research will have relevance to our understanding of the effects of E on the adaptive functioning of the organism in adulthood.